Lymphokines, the hormones of the immune system, have the potential to influence the development of cancer, to suppress the growth of tumorigenic cells, and even to destroy tumors. These hormones are glycoproteins, produced and secreted by certain types of lymphoid cells and targeted to interact with other specific cells. Particular lymphokines are known to be produced by and able to interact with more than one type of cell. Similarly, the activities of most lymphokines are known to be multifaceted; a particular lymphokine displaying inhibiting, stimulating, enhancing, contravening and other activities with respect to various target cells and conditions. Moreover, a particular lymphokine may act to both inhibit and enhance carcinogenesis under different circumstances. For example, interferon is known to inhibit viral carcinogenesis but enhance radiation carcinogenesis. Similarly, interferon exhibits the antagonistic activities of increasing the NK cell lysis of tumor cells, while increasing tumor cell resistance to NK cell activity; the former occurring earlier in time after exposure to interferon than the latter.
Lymphotoxin is a term introduced in 1968 to denote the soluble product of antigen or mitogen stimulated lymphocytes that mediate the cytolytic destruction of mouse L cells (9). Several laboratories subsequently demonstrated that lymphokine preparations containing lymphotoxin had direct-acting cytolytic and cytostatic activities against a variety of tumor cells (7,30,31), anti-carcinogenic activity toward cells undergoing neoplastic transformation (6,25,26), and the ability to enhance the sensitivity of preneoplastic and neoplastic cells to NK-mediated destruction (23,27).
An anticancer lymphokine in hamster lymphotoxin preparations distinct from that mediating mouse L cell cytolytic destruction was later identified on the basis of molecular charge (24). That 50,000 molecular weight molecule with an isoelectric pH of 5.0 was cytostatic for hamster tumor cells, did not inhibit the growth of normal hamster fetal fibroblasts, and inhibited the chemical and radiation-induced neoplastic transformation of hamster fetal cells, both in vitro and in vivo. The unique anti-cancer lymphokine was also identified as being distinct from interferon, interleukins 1 and 2, and macrophage migration inhibitory factor activities. This discovery ultimately led to a new course of research, wherein human lymphotoxin preparations were investigated to assess whether human lymphotoxin preparations contained human lymphokines having unique anticarcinogenic and antitumor properties.